Fluorine-18 (F-18), which is the most widely used positron emission tomography (PET) substance, is generally obtained from cyclotron and supplied in dissolved form, i.e., supplied as fluoride which does not bear chemical activity. Accordingly, in aqueous solution, F-18 can hardly label biologically active substance. Therefore, the general process involves removal of water, addition of tetrabutyl ammonium or crown ether, and reaction with precursor with good leaving group and organic solvent, which enables F-18 activation and labeling.
In order to remove water to prepare positron-emitting radiopharmaceutical product with F-18 labeling, generally, heating to bubble the gas, or evaporating in reduced pressure, are used. However, there are shortcomings. That is, the necessity for 1 to 10 mL or larger container hinders space-efficiency of the automatic synthesizing equipment, and time consumption for water evaporation that is longer than the other processes is another shortcoming. Accordingly, many have studied on methods for labeling F-18 which does not require water removal process.
Certain frontier suggestion was made by Immunomedics, Inc., as disclosed on WO 2008/088648, US 2008/0253964, US 2009/0155166 and a series of non-patent documents including: McBride W J, et al., “A novel method of 18F radiolabeling for PET” (J Nucl Med (2009) 50:991-998); Layerman P, et al., “A novel facile method of labeling octreotide with 18F-fluorine” (J Nucl Med (2010) 51:454-461); and McBride W J, et al., “Improved 18F labeling of peptides with a fluoride-aluminum-chelate” (Bioconjug Chem (2010) 21:1331-1340)). According to the above method, complex of F-18 and aluminum is first formed, and then chelate is formed on NOTA derivative attached to bioactive substance such as octreotide. Because the reaction occurs in aqueous solution, water removal process can be omitted, thus providing advantage such as simpler reaction process and faster rate.
However, although the F-18 labeling method proposed by Immunomedics Inc. provides more economic ways to label F-18 thanks to omission of water removal process, the labeling efficiency is limited to around 50% and this has to be actively improved.
While studying ways to improve labeling efficiency, the present inventors were able to synthesize novel triazanonane derivatives and confirm that the triazanonane derivatives provide effect of improved F-18 labeling efficiency, and therefore, completed the present invention.